A somatic-cell genetic approach for the study of the control of chromosome replication in mammalian cells is proposed. It has been demonstrated that there is a difference between the order of termination of chromosome replication in human lymphocytes and skin fibroblasts from the same individual. Some of the human chromosomes remaining in a human fibroblast-mouse cell hybrid have an altered replication pattern, relative to the same chromosomes in the parental fibroblasts. An autoradiographic analysis of the terminal sequence of replication will be done on somatic cell hybrids and microcell hybrids with different complements of human chromosomes, to determine whether the altered patterns result from the absence of the intact human genome or from the presence of the mouse nucleus. The timing of replication of single human chromosomes in mouse-human hybrids will also be analyzed. The replication of specific regions of chromosome which exhibit different replication patterns in various cell types will be analyzed by the BUdR-Hoechst 33258 technique. The relationship between patterns of initiation and termination of replication will be examined. The order of initiation of chromosome replication will be studied in lymphocytes, fibroblasts, and hybrids. The effects of blocking and releasing cells at the beginning of the S-phase on the order of terminal replication will be studied. The replication patterns of the chromosomes in transformed cells will be studied and compared with those of normal cells of the same types. These experiments will be done on EBV-transformed lymphoblastoid cells and on SV40-transformed fibroblasts. If abnormal patterns are found, hybrids containing these chromosomes will be studied to determine whether the aberrations are reversible in the absence of other chromosomes from the transformed cells. The timing of replication of specific regions of autosomal translocations will also be examined in skin fibroblasts to determine whether there are position effects which alter the normal sequence of replication.